Mechanisms of wound healing and tissue repair in humans and in other animals are often inadequate and incomplete. Wound healing is often substantially impaired in the elderly, in cancer patients after chemotherapy or radiation treatments, in persons with diabetes, and in individuals suffering from severe burns. The lesions caused by auto-immune diseases such as Krohn's disease or osteoarthritis are also characterized by slow and deficient healing. In general, poorly healed wounds are characterized by necrotic regions which rapidly become infected, causing pain and suffering to the person and requiring additional medical treatment. Even when such wounds finally heal, the "wound area" is often devoid of the ability to respond to tactile stimulus and is often filled with excessive deposits of collagen that lead to uncleared scarring.
Wound healing is a highly precise biological process initially exemplified by an invasion of cells of the immunological system and fibroblastic cells which secrete the structural protein collagen into the wounded area. Later, blood and lymphatic vessels reform, and nerve axions infiltrate the wound area. A currently incomplete understanding of the biological processes regulating the healing process if reflected by the relative inadequacy of present treatment methods.
Current methods of treatment of wounds include the use of a type of nerve growth factor to accelerate the wound healing process (U.S. Pat. No. 4,287,184), a mixture of albumin-freed cap serum and vasodilatory peptides (kinins) (U.S. Pat. No. 4,177,261) and the use of partially digested bovine casein, polyvinyl pyrrolidine and carrageenan as a healing aid (U.S. Pat. No. 3,558,770). Other treatments include the use of emulsified aqueous mixtures of bovine gelatin, sucrose, corn syrup, oatmeal, and other salts in order to provide a protective covering for wounds, as in U.S. Pat. No. 3,767,784, and the use of egg shell membrane products, as in U.S. Pat. No, 3,194,732.
With regard to all of the above cited wound-healing formulations, immunological considerations suggest that the foreignness of the components in these formulations would most likely elicit an antibody recognition and subsequent inflammatory response in any animal except the donor species. In hypersensitive or allergic animals or human patients, such responses can often be lethal.
The most promising compositions to date which have proven to accelerate the healing of a wide variety of wounds and tissue injury are a class of compounds called superoxide dismutases, compounds that possess a biochemical ability to detoxify a highly-reactive tissue-damaging oxygen radical called superoxide anion. The healing of many types of traumatic tissue damage and of aging associated degenerative conditions is delayed by the excessive production of superoxide anion. After wounding or dramatic tissue injury, cells of the immune system invade the damaged area and secrete copious quantities of toxic oxygen radicals to kill invading bacteria. In a similar manner, in auto-immune diseases, the immunological cells also secrete oxygen radicals into the afflicted area, ostensibly to kill infective organisms, and thereby induce tissue damage and localized inflammation.
Often in cases of impaired healing, the production of superoxide anion further damages tissues and brings in a new influx of immunological cells, thereby creating a vicious circle of damaging events which can greatly delay the normal sequence within the healing process. To obtain proper healing of damaged tissue, it is generally necessary to terminate the production of superoxide anion in the afflicted area.
A number of biological and synthetic molecules catalyze the breakdown and toxification of superoxide anion, some of which have proven to possess clinically useful properties that promote healing and reduce inflammation. However, all such molecules have substantial deficiencies which sharply limit their clinical efficacy.
One approach has been to use certain low molecular weight copper chelates, such as salicylate-copper or diisopropylsalicylate-copper, which possess superoxide dismutase activity. While these complexes also possess anti-inflammatory and healing actions, they tend to dissociate after injection, since the binding affinity of the organic component for copper is too low to retain the copper under physiological conditions. In addition, these small copper complexes tend to be poorly soluble under aqueous conditions and must be administered with tissue-irritating solubilizing agents. Another of these copper chelates, the penicillamine-copper complex, often produces skin rashes and a personality change known as "penicillamine psychosis."
Another compound exhibiting superoxide dismutase activity, with a molecular weight of approximately 33,000, is the copper and zinc chelate known as Orgotein. Orgotein possesses anti-inflammatory and anti-trauma properties, and is thought to accelerate the healing of hemorrhoids, frost bite, skin abrasions, soft tissue injuries, and tissue damage associated with auto-immune diseases such as arthritis and Krohn's disease. Orgotein has been isolated from bovine tissue as described in U.S. Pat. Nos. 3,758,682 and 3,832,338 and esterified Orgotein has been described in U.S. Pat. No. 4,022,888. However, Orgoteins evoke an antigenic response in humans, and when therapeutically applied, exert their action in the extra-cellular tissue compartment as opposed to penetrating into the cells themselves.
Consequently, there exists a need in the art for an effective, non-toxic method of enhancing the wound healing process and reducing inflammation, which further does not evoke an antigenic response.